Biomarkers of quercetin-mediated modulation of colon carcinogenesis

Colorectal cancer (CRC) is hypothesized to be prevented by intake of fruits and vegetables that contain anti-carcinogenic compounds, including theflavonoidquercetinthat is found in apples and onions. In this thesis,quercetin'smechanisms of cancer-preventive action were studied both in vitro and in vivo . The in vitro experiments were performed using the human Caco-2 cell line as a model for CRC, andquercetinstabilized byascorbatein the culture medium. Unexpectedly,ascorbate-stabilizedquercetinshowed enhancement of cellular processes involved in CRC-development, including stimulated cell proliferation, reduced cell differentiation and enhancement of pathways that stimulate cell survival. Furthermore,transcriptomicsshowed thatquercetindownregulatedexpression of genes involved intumorsuppression and phase II metabolism, andupregulatedoncogenes. Comparison with Caco-2 cells exposed toquercetinin the absence ofascorbateshowed the opposite, i.e. anti-carcinogenic effects by thisflavonoid. This led to the hypothesis thatquercetin-induced reactive oxygen species that eradicatetumorcells were scavenged by vitamin C, causingtumorcell survival. Withoutascorbate, these reactive oxygen species may be responsible for anti-carcinogenic effects, pointing to beneficial effects of supposed adverse reactive intermediates.Subsequently, the CRC-modulating potency ofquercetinand its conjugaterutinwere investigated in a rat model for CRC.Quercetin, but not its conjugaterutindecreased thetumorincidence, which was associated with the blood plasma levels of this anti-oxidant, but not reflected by the putativepreneoplasticbiomarker lesions, designated aberrant crypt foci. The combination oftranscriptomicsand proteomics showed thatquercetininhibited the potentiallyoncogenicmitogen-activated proteinkinase(Mapk) pathway and enhanced expression oftumorsuppressor genes, cell cycle inhibitors, and genes involved inxenobioticmetabolism. In addition,quercetinaffected the energy production pathways, by increasing mitochondrial fatty acid degradation, and inhibitingglycolysis. This observation provided a new hypothesis pointing at another anti-carcinogenic mechanism forquercetin, based on an alteration in routes for energy metabolism, shifting them infavorof non-tumorlike pathways like mitochondrial fatty acid degradation at the cost of thetumor-likeglycolyticpathway for cellular energy supply.Overall, the studies presented in the present thesis provided new hypotheses for the mode of action ofquercetinas an anti-tumoragent, but it appeared that the actual dose needed to exert this beneficial effect amounted to about 60 - 100 times the already relatively high prescribed dose forquercetinsupplements. Therefore, it is concluded that health claims on the use ofquercetinas an anti-cancer agent need better scientific support.

Bibliographic Details

Main Author:	Dihal, A.A.
Other Authors:	Rietjens, Ivonne
Format:	Doctoral thesis biblioteca
Language:	English
Subjects:	biochemical markers, colorectal cancer, quercetin, biochemische merkers, colorectaal kanker, quercetine,
Online Access:	https://research.wur.nl/en/publications/biomarkers-of-quercetin-mediated-modulation-of-colon-carcinogenes
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